The common occurrence and serious outcome of prostate cancer (PCa) skeletal metastases has risen to the forefront of public concern and subsequently the NCI. In the first three years of this program award, we have addressed this important issue, resulting in over 50-grant-related publications. In the current competitive renewal, we continue to attack this problem by combining leading expertise in PCa research and bone metabolism. The ultimate goal is to define the cellular and molecular mechanisms that surround PCa skeletal metastases so as to set the groundwork for translation into clinical applications. The central theme of this Program is that there is crosstalk between PCa cells and the bone microenvironment that foster the development and progression of PCa metastasis. This crosstalk promotes the ability of PCa cells to migrate, attach, and manipulate the cells in bone thus enhancing the tumor's capacity to alter the bone microenvironment to render it conducive to tumor growth. To expand on this theme the Program encompasses closely interrelated hypotheses of four scientific projects supported by three cores. Project 1 explores the novel concept that the similar to an endocrine organ, the primary PCa modulates the distant bone marrow, in part through production of CCLZ, to make it conducive for receiving metastatic PCa cells; Project 2 examines the exciting idea that PCa cells co-opt the hematopoietic stem cell (HSC) niche in the bone marrow; Project 3 explores the unexpected role of the Wnt inhibitor Dickopff as a molecular switch that promotes the osteoblastic phenotype of PCa; and, Project 4 investigates the novel hypothesis that PCa, through PTHrP, modulates osteoblasts and HSCs leading to angiogenesis in the bone microenvironment that promotes PCa progression. These projects will be supported by three integral cores: Core A (Administration) that will coordinate reporting, evaluation, and committee activities, facilitate interactions among the projects and provide biostatistical support; Core B (Animal) provides mouse models and imaging and assistance with their use and Core C (Bone) provides expertise with bone histology processing and interpretation. This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research on PCa bone metastases.